Clinical Trials for Otoprotective Agents

Researchers Investigate Drugs to Prevent and Treat Hearing Loss

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Audiologists know the frustration of fitting hearing aids on patients who have noise-induced hearing loss, only to have them say at follow-up that they still cannot hear in their favorite social settings. They have a point—it's a noisy planet!

Roaring motorcycles, screaming sirens, and, of course, those ubiquitous little "buds" in so many ears can damage hearing over time. Who hasn't had "stuffy" ears, or even tinnitus, after attending a rock 'n' roll show or some other loud event? Military personnel routinely experience high noise levels during training and on the battlefield. It's no wonder noise-induced hearing loss is one of the most common occupational disorders (Nelson, Nelson, Concha-Barrientos, & Fingerhut, 2005).

But the number of people with hearing loss from noise could change with the development of new otoprotective drugs entering clinical trials under the oversight of the U.S. Food and Drug Administration (FDA) through the Investigational New Drug application process. Within the next few years, we hope one or more of these—or other—otoprotective agents will succeed in clinical trials and go on to win FDA approval for prevention of hearing loss.

There also are a number of agents in the early stages of preclinical development. Currently, no drug is approved by the FDA to prevent or treat any type of hearing loss or tinnitus. If even one of these drugs ultimately receives approval for clinical use, it could improve patient outcomes worldwide.

Free Radicals and Cell Death

Noise, cisplatin (used to treat a variety of cancers), and aminoglycoside antibiotics all share some common mechanisms in how they affect the inner ear's cells. They induce oxidative stress and accumulations of free radicals—molecules with unpaired electrons—in the sensory cells, supporting cells, and lateral wall, ultimately leading to cell death and acquired hearing loss. Charged molecules are harmful if they bind with other charged molecules in the lipid membranes or other cell structures.

The good news is that if these toxic free radicals react with certain other charged molecules—antioxidants—the charged status of the free radicals can be neutralized without harming cell structures.

Several antioxidant defense systems—including superoxide dismutase, catalase, and glutathione—provide protection against free radicals. Glutathione, for example, donates hydrogen atoms to stabilize charged free radical molecules. This process leaves glutathione in a charged state, but these charged glutathione molecules tend to bind with each other, resulting in a stable compound—glutathione disulfide. That compound can be "recycled" back into an active glutathione molecule by other enzymes, leaving it ready to donate another hydrogen atom to stabilize another free radical.

With these facts in mind, researchers are assessing the otoprotective and rescue qualities of various agents for three primary applications: noise-induced hearing loss and tinnitus, cisplatin-induced hearing loss and tinnitus, and aminoglycoside-induced hearing loss, tinnitus, and balance disorders. On all three fronts, our ever-increasing knowledge of the mechanisms of cell death has spurred progress in otoprotectant research (Campbell & Le Prell, 2012).

Protection From Noise

Given the worldwide prevalence of noise-induced hearing loss (Nelson, Nelson, Concha-Barrientos, & Fingerhut, 2005), it makes sense to prioritize the development of agents that protect against it. Many years of laboratory research support a variety of agents, but prevention of noise-induced hearing loss and tinnitus is the area furthest along in development.

N-acetylcysteine (NAC), the active agent in "The Hearing Pill"™ (marketed by American BioHealth Group), was tested previously in two clinical trials, but researchers observed no clinically significant protection (Dolgin, 2012). New studies are assessing the potential benefit of NAC in combination with other agents that reduce free radical insult.

Researchers and clinicians hope that D-met, ebselen, and ACE Mg—or other agents that have not yet entered clinical trials—will ultimately be shown to provide clinically significant benefits. In animal models, some agents can be started hours, or even days, after a noise exposure and still provide protection. This discovery could be useful for unexpected noise exposures. An opportunity to provide post-noise "rescue" would be appealing indeed!

Protection From Ototoxicants

Life-saving drugs can defeat cancers and infection. But unfortunately, these therapies can come at the expense of permanent hearing loss.

Cisplatin is a well-known ototoxicant. Aminoglycoside antibiotics—used in the United States to treat multidrug-resistant tuberculosis and the aggressive and recurrent infections common to patients with cystic fibrosis—also induce hearing loss. These antibiotics are cheap and readily available, and thus serve as drugs of choice in developing nations.

Several agents are in or approaching clinical trials for the prevention of cisplatin- and/or carboplatin-induced hearing loss. The first, delayed sodium thiosulfate (STS), given simultaneously with cisplatin, reduces the anti-tumor action of chemotherapy. Therefore, some clinical trials are providing STS several hours after cisplatin chemotherapy to determine if it reduces hearing loss. Researchers tested D-met in one small-scale clinical trial (Campbell, Rybak, Meech, & Hughes, 1996), and demonstrated that it did protect against cisplatin-induced hearing loss (Campbell & Le Prell, 2012; Dolgin, 2012). Further larger-scale, multicenter clinical trials are being planned. Clinical trials with ebselen and NAC are in the planning stages (Campbell & Le Prell, 2012; Dolgin, 2012).

Aminoglycoside-induced hearing loss has received less attention, but is a problem for patients receivingrepeated aminoglycoside antibiotic therapies. The only agent in the planning stages for clinical trials is D-met, although other agents have demonstrated some protection in early-stage preclinical studies.

The next five to 10 years should see several otoprotective agents go through the FDA clinical trial process. And we hope, within that same timeframe, one or more agents will be available to clinicians trying to prevent various types of drug- and noise-induced hearing loss and tinnitus.

Until clinical trials are completed and FDA approval is obtained, it is difficult to predict whether these protective agents will be routinely taken in advance of a drug or noise exposure, or used only for high-risk situations or in people who already have a hearing threshold shift. Our audiologic practice may change as we become involved in these decisions.

In the future, when a chemotherapy patient experiences a hearing shift, you might be able to recommend an otoprotective agent to preserve hearing. People who work in noisy environments, exposing their ears to industrial noise over the course of a working lifetime, could take a daily pill. Others might opt for a short-term therapeutic approach, limited to a few days before and after attending a rock concert. Or better yet, maybe we can prevent hearing loss in the first place, an option we haven't had before.

Kathleen C. M. Campbell,
PhD, CCC-A,
is professor and director of audiology research in the Division of Otolaryngology-Head and Neck Surgery, Departments of Surgery and Pharmacology, at the Southern Illinois University School of Medicine. Her research interests include ototoxic and noise-induced hearing loss and pharmacologic otoprotective agents. Contact her at kcampbell@siumed.edu.

Colleen Garbe Le Prell,
PhD,
is an associate professor in the Department of Speech, Language, and Hearing Sciences at the University of Florida. Her primary research interests include prevention of acquired hearing loss. Contact her at colleeng@phhp.ufl.edu.